Packaged products, inserts and compartments for aseptic mixing of substances, along with methods for use therewith

ABSTRACT

A package comprising a container for holding a first substance, and a product insert for holding a second substance, at least partially inserted info said container, and where the first product and the second product can be allowed to merge by external manipulation of said package. Packaged products and methods are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. application Ser. No.61/143,971 filed on Jan. 12, 2009. The present application also claimsthe benefit of U.S. application Ser. No. 61/261,315 filed on Nov. 14,2009. The disclosures of each of the above applications are incorporatedherein by reference in their entireties for all purposes.

FIELD

The present invention relates generally to packages with mixingcapability of more than one substance, and more particularly to asepticpackages with aseptic mixing capability.

BACKGROUND

Aseptic prefilled packages are commercially available and commonly usedin the medical, cosmetic and food industries as well as in applicationsoutside of this field. aseptic packages provide a hermetic barrierbetween the product contained therein and the exterior of the package tominimize or avoid environmental exposure, exposure to contaminants, andpermeation of gasses and moisture.

In various applications it is desired to deliver the contents of theaseptic package outside of the package and such packages will beequipped with a fluid transport device for such purpose. Also, in someapplications it is desired that the aseptic package will function as adispenser of the contents therein, and to do so the aseptic dispensingpackage is equipped with a fluid transport device in the form of an exitport furnished with the applicable applicator such as a nozzle, spout,dropper, spray-head, topical applicator, ocular or ear applicatorcannula, needle, micro-needles, or an adaptor (including connector,fitting, tube, hose or sealing member) to connect to the desiredapplicator or device. In a common arrangement the applicator is confinedwith in the aseptic package such that it is exposed to the productcontained in the package but protected from the surroundings by the samebarrier and to the similar extent as the product. The applicator iscommonly either an integral feature of the package formed in the processof making the container, or inserted into the package either during theprocess of forming the package, before filling the package, or afterfilling the package. Aseptic packages are further commonly equipped withmeans for breaking the integrity of the aseptic package to expose theapplicator, preferably without getting the applicator contaminated bythe user hands or the exterior side of the package. A number ofmanufacturing methods have been developed over the year to form, filland seal the package on a single piece of equipment.

Examples of aseptic dispensing packages include BottlePak® asepticcontainer products line by Rommelag® from Waiblingen, Germany.BottlePak® utilize a blow-fill-seal process to form fill and seal apackage in a single machine in aseptic conditions (hereafter some timesreferred to as “BFS” process). BFS method generally comprise thefollowing steps: a) Extruding—a plastic parison, extruded from polymer,is accepted by the opened blow mold and cut below the die of the parisonhead, b) Molding—the main mold closes and simultaneously seals thebottom. The special mandrel unit settles onto the neck area and formsthe parison into a container using compressed air or vacuum, c)Filling—by the way of the special mandrel unit, the product preciselymeasured by the dosing unit is filled into the container, d)Sealing—after the special mandrel unit retracts, the head mold closesand forms the required seal by vacuum, e) Mold Opening—with the openingof the blow mold, the containers exits from the machine and the cyclerepeats itself. BottlePak® containers are sometimes equipped with atwist off portion that, when twisted off, expose an applicator which wasintegrally formed with the package. Such BottlePak® products includesingle dose eye drops ampoules with a pointy dropper tip or smallparenteral containers with Luer-Lock connector (see more athttp:/www.rommelag.com/en05 applications/05 other pharmaceutical.html).Some BottlePak® products comprise an insert which is inserted into thepackage post-filling and prior to sealing in proximity to the twist-offfeature, such that upon twist off of the breakable portion of thepackage, the insert is exposed and facilitates the dispensing of theproduct contained in the package (here after “Blow-Fill-Insert-Seal”process or “BFIS”). Examples of such products include an approximately 3ml bellows-structure squeezable container comprising a stainless steelcanula insert for hypodermic administration. Another example ofBottlePak® BFIS product is a 1 infusion bottle comprising a rubberseptum to which an infusion set can be connected via a spike. The abovemanufacturing method is taught by U.S. Pat. Nos. 7,192,549, 7,004,213,5,836,922, 5,687,550.

Similar BFS and BFIS products to the BottlePak® products are availablefrom Weiler® (Elgin, Ill.) http://www.weiler-bfs.com/asep-techsystems/applications.html.

Further aseptic packages similar in form and function to BFS and BFISunit dose containers are manufactured by Form-Fill-Seal process (“FFS”)and are available from Sarong, Italy (www.sarong.it) and Unifil fromVillafranca Di Medolla, Italy (www.unifil.it). FFS method forms theindividual packages from continuous film strips which are thermoformed,partly sealed, filled, and then sealed on a single piece of equipment.An insert can be introduced to the package after the forming step andprior to the sealing step (pre or post filling) or after sealing thepackage.

Similar aseptic packages are manufactured by injection molding of astrip of several packages or individual packages which are filled fromthe back side (i.e. not the dispensing side) and sealed in subsequentsteps. An insert can be incorporated in the package during or post theinjection molding step. Such packages and equipment for making suchpackages are available from Lameplast® Rovereto di Novi, Italy(www.lameplast.it), and Sanner Plastic Technology from Bensheim, Germany(www.sanner.de).

If sterility of the product is desired it can be achieved by eitherperforming the production in aseptic and sterile conditions usingpre-sterilized raw-materials, components and substances, or bysterilizing the product after production or after a certain productionstep, or by a combination of the above approaches.

In some applications it is desired that an aseptic package will includemore than one substance compartment such that the plurality ofcompartments could be mixed to form a product prior to dispensing. Innon-aseptic applications several methods could be applied to open anumber of compartments or separate packages and to introduce the contentof one package or compartment to another to formulate a product. Forexample hair-dye products such as Just-For-Men from www.justformen.comcome in a retail package containing two bottles where the contents ofsaid packages need to be mixed prior to application. One of said bottlescomprise enough free space to receive the content of the second packagesuch that the procedure of preparing the product is a) to remove theclosures from both bottles, b) pour the content of the smaller bottleinto the larger bottle, c)agitate, and dispense. While the method ispractical, simple and does not require any dedicated package design oradditional equipment, such a method will not be acceptable forapplications where aseptic conditions are to be maintained until andduring application (dispensing).

Several patents disclose caps for mixing a substance stored in the capwith the content of the container to which said cap is mounted. U.S.Pat. No. 7,464,811 teaches a mixing cap comprising an apertured innertube threadably-engagable to the mouth of a bottle, and an outer housingcooperatively-engaged to the inner tube and slidably-restrictedthereover via a flange arrangement. Preloaded ingredients containedwithin the outer housing may be introduced or discharged into the bottleby simply depressing the outer housing over the inner tube, therebypermitting the ingredients to flow through the apertures of the innertube and into the liquid contents of the bottle. The combinedingredients and liquid within the bottle may subsequently be shakenwithout fear or risk of leakage or spillage. This mixing solution aswell as many of the mixing caps known in the art suffer from two maindisadvantages: a) the substance in the cap is not guarded at the samelevel of isolation from the environment as the product in the container,and b) in the procedure of merging the contents of the cap and thecontainer the aseptic integrity of the package in breached (in the caseof U.S. Pat. No. 7,464,811 the slideable part of the cap slides down toinclude an external portion of the cap in the sealed product space.

Various solutions have been developed for aseptically mixing theproducts of two compartments of a package. One advantage of suchpackages is that they provide longer shelf life and/or are moretolerable to storage conditions where the combination of the products ofthe two compartments suffer from accelerated deterioration or issensitive to conditions such as temperature or exposure to light, or toavoid interaction between a substance in the first compartment with asubstance in the second compartment. In other applications the productsof the two compartments react as a desired step of the application andmust be maintained separately such that the reaction occurs only before,during or immediately after the application (dispensing).

U.S. Pat. No. 7,025,200 to Fontana discloses a bottle for two-componentextemporaneous products, of the type that comprises: a container for afirst component, which is provided with an upper mouth; a reservoir forcontaining a second component, which is inserted substantially coaxiallyin the mouth, is open upward and has a bottom constituted by adiaphragm; a perforator, which can be inserted in the reservoir and isadapted to pierce the diaphragm in order to mix the two components; anda removable cap for closing the container in an upward region; the capcomprises a lower annular portion that is fixed to the container and anupper cylindrical portion that cooperates with the perforator and isrigidly coupled to the annular portion at an intermediate weakenedregion suitable to act as sealing means, a downward pressure on thecylindrical portion being adapted to disengage it from the annularportion and to make the perforator slide in the reservoir in order topierce the underlying diaphragm. Various alternative approaches aredisclosed in prior art including U.S. Pat. Nos. 3,968,872, 5,029,718,5,543,097, 5,884,759, 6,148,996, 6,435,341 differing to some extent bythe mechanism details, steps, and actions needed to cause twocompartments to mix. The inventor of the current invention believes thatthose prior art approaches suffer from some common drawbacks:

-   -   a) Seal Quality—the seal between the first compartment and the        second compartment, and the seal between at least one of the        compartments and the environment is achieved either by press-fit        or through at least portions by thin molded plastic wall. As        used herein, the term press-fit seal in this patent refers to a        seal caused by forcing two semi elastic components against each        other such that a deformation is caused to a circumferential        contact line between said two components to prevent migration of        substance through this contact line. A surface stress remains        along this contact line due to the elasticity of the components        that maintain the seal even if reasonable pressure or force is        biasing against that function of the seal. The term molded        plastic component refers to components manufactured by either        injection molding or blow molding or similar methods or by        methods incorporating one of those methods. The wall of molded        components have limited moisture barrier properties and        therefore where the product in the one compartment is water or a        solution and the product in the other compartment is super-dry        powder or solid in other forms which needs to maintain in super        dry conditions, molded components can not provide the required        barrier for an extended time. The same drawback exists with        press fit seals.    -   b)Another disadvantage of the prior art is that it can not        support aseptic delivery (i.e dispensing, application,        administration, etc). Because these packages are designed to be        aerated as the content is expelled. Alternatively, though not        proposed by their inventors, the packages in the prior art could        be squeezed to cause the content to expel without air        penetrating the package. The drawback there is that the        arrangements in those different approaches would not allow an        efficient expression rate of the content since those        arrangements occupy or stiffen a substantial portion of the        package that could not be squeezed.

The drawbacks listed above are partly overcome by U.S. Pat. Nos.6,203,535, 5,176,634 and 6,996,951, 4,602,910, 5,462,526, 5,287,961,4,961,495, 4,608,043, 5,425,447, 3,749,620, 6,017,598, 3,074,544,3,608,709, 3,847,279, all of which disclose a film package comprising atleast a first and a second compartment separated from each other by afrangible seal (some times referred to as peelable seal) such that underthe presence of pressure in at least one of said two compartments thefrangible seal separates causing the content of the two compartments tomix. In particular Smith's U.S. Pat. No. 5,176,634 teaches a flexiblecontainer is provided for the storage and mixing together of diluentsand medicaments. The container incorporates multiple compartments,separated by frangible seals, in which the diluents and medicaments arestored. The seals are ruptured by manipulation of the container tothereby mix the contents together for delivery through a standard IVarrangement to a patient. The express ratio of such packages is high asthere is not much resistance or obstacles to prevent the package fromefficiently collapsing. The seal is formed by a weld between two wallsof said film package with substantial weld-width resulting in goodmoisture barrier properties. While these approaches overcome some of thedrawback of the prior art they lack the ergonomic properties that therigid containers of the first group of prior art listed above. Forseveral applications flexible packages do not meet the common form ofpresentation, for example in the field of infusion containers theEuropean Market is customary to semi rigid bottles rather than theinfusion bags which are more common in other parts of the world.

US Patent Application Publication No. 20060276755 teaches a valvedmedicament delivery device including a housing having a chamberincluding coaxially aligned inlet and outlet, a medicament cartridgelocated within the chamber having a passage therethrough and membranessealing the passage having a burst pressure of less than 10 atmospheres,a manually actuatable fluid delivery device having an outlet in fluidcommunication with the chamber and a manually actuated valve locatedbetween the outlet of the fluid delivery device and the chamber inletfor delivery of fluid under pressure to the valve. The medicamentdelivery device of this invention may be utilized to deliver acontrolled unit dose of a medicament on demand by first pressurizing apressure chamber in the pressure delivery device upstream of the valve,then opening the valve to open the membranes and express the medicamentthrough the chamber outlet. In this patent the second compartment withthe second substance is external to the syringe with the first substancethus the mixing of the two compartments occurs when the environment isno longer inherently aseptic. In addition this patent teaches a methodof first mixing the first substance and the second substance but insteadthe dispensing occurs simultaneously with mixing.

It is therefore an intention of the present application to provide amulti-compartment chamber which can provide high barrier propertiesbetween said compartments, have good expression rate, yet allow for theergonomics of a molded package and could be manufactured in a methodthat reduces contamination risks.

SUMMARY

A packaged product is provided and comprises at least one containerstoring a first substance and a substance insert storing a secondsubstance that is at least partially stored within the container. Atleast a portion of the substance insert comprises a flexible barrierbetween the substances. When integrity of the flexible barrier isjeopardized by external aseptic manipulation of the packaged product,the first and second substances are allowed to merge.

In some arrangements, the substance insert comprises a frame which maybe rigid or semi-rigid. The frame may be a deformable member whichsupports a susceptible portion of the flexible barrier to translatedeformation of the container into a resulting force on the flexiblebarrier, or to translate pressure applied to the flexible barrier intoan applied force on the susceptible portion. In some arrangements,deformation of the frame translates into movement of the secondcompartment which damages the flexible barrier, such as breaking itsseal or rupturing it, to permit the first and second substances tomerge.

The substance insert is partially or entirely disposed within thecontainer, and one or more such inserts may be provided. Duringmanipulation of the packaged product, at least a portion of thesubstance insert may move to reduce the volume of the secondcompartment. In some arrangements, the substance insert comprises apouch which contains the second substance. In other arrangements, ablister pack is provided. Still in other arrangements, the substanceinsert comprises a plunger assembly movably disposed within thecontainer between a pre-activation position, wherein the first andsecond substances are separated by the flexible barrier, and anactivation position, wherein integrity of the flexible barrier isjeopardized to allow merger.

Preferably, an interface mechanically engages the substance insert withthe container, for example, via a bond, a weld, a mechanical interlockor any combination thereof, to provide a fluid tight seal. The interfacesupports the flexible barrier to cause the integrity of an acceptableportion of the barrier to be jeopardized by pressure or movement of thesubstance insert. In various embodiments, the substance insert isengaged with the container via an interface that remains attached to thecontainer in a fluid tight seal during customary use of the packagedproduct.

In an exemplary embodiment, the container comprises a first compartmentfor storing the first substance, and the substance insert comprises asecond compartment for storing the second substance. Preferably, thesecond compartment also provides the flexible barrier. In somearrangements, a third compartment stores a third substance to be mergedwith one or both of the first and second substances. The thirdcompartment may substantially encapsulate the second compartment tosurround it with a desired environment. In some arrangements, the thirdcompartment is separated from the first compartment by a substanceinsert interface.

The flexible barrier may be a film; a foil; a laminate; a multi-layerproduct combining films, foils and laminates; an injection moldedportion; a blow molded portion; or any combination thereof. The barriermay be jeopardized in a variety of ways, such as breaking a frangibleseal or through rupturing the barrier. This may be caused by movement ofthe substance insert or pressurization of one or more of the first andsecond substances. The flexible barrier is supported such that pressureor movement of the substance insert jeopardizes a susceptible portion ofthe barrier.

In some arrangements, a fluid transport device (FTD) is provided fordispensing the merged contents of the container. The FTD may have avariety of configurations such as a topical applicator, a spray head, asquirt nozzle, a dropper nozzle, a nasal applicator, an oral applicator,an aural applicator, an invasive applicator, a connector, or anysuitable combination thereof. The FTD, itself, may be an insert that isdisposed entirely within the container and, in some arrangements, aremovable guard aseptically protects the FTD from an ambientenvironment. The product may also comprise a FTD disabler frompreventing continued use of the FTD, as appropriate or desired. In somearrangements, the substance insert and the FTD are a common insert. Insome arrangements, the substance insert and the FTD are locatedproximately to, or distally from one another. In some arrangements, atleast a portion of the FTD is inserted into the container, while inother arrangements, at least a portion of the FTD is integrally formedin the container. In the various embodiments, the FTD allows forintroduction of a substance into either the container or the substanceinsert.

The container may assume a variety of configurations. In someembodiments, the container is configured generally in the shape of abottle which comprises the first and second storage compartments and aneck portion. The substance insert may be accommodated partially orentirely within the neck portion. Preferably, the substance insert issupported relative to the neck portion such that deformation of the neckportion results in a corresponding deformation of the substance insert.A separate actuator may be employed to deform the neck portion in thisregard. In the bottle configuration, as well as other configurations,the container may comprise an inlet FTD for receiving the firstsubstance and an outlet FTD for dispensing the merged containercontents. The inlet and outlet FTDs may be the same. Otherconfigurations provide a container in the form of a squeezer tube. Thecontainer may be formed by one of injection-molding, blow molding,blow-fill-sealing, blow-fill-insert-sealing, form-fill sealing, andinjection-blow-molding, for example.

Arrangements are also provided for a substance insert for use in apackaged product that includes an integrally sealed container withinwhich the insert is intended to be at least partially inserted. Broadly,the substance insert comprises (1) a compartment storing a substance;(2) a container interface for confronting a wall of the container,wherein the container interface comprises a first material; and (3) aflexible barrier comprising a second material different from the firstmaterial whereby sufficient external manipulation of the container willjeopardize the integrity of the flexible barrier without jeopardizingintegrity of the container, thereby to allow the substance to bedispensed from the compartment. Another exemplary embodiment of asubstance insert comprises (1) a compartment storing a substance; (2) acontainer interface for confronting a wall of the container; and (3) aflexible barrier supported by the container interface to deliver force,whereby sufficient external manipulation of said container will causethe container interface to affect force to the flexible barrier whichwill jeopardize an integrity of the flexible barrier.

The compartment for the substance insert, the container interface, andthe flexible barrier may assume one or more of the differentarrangements and combinations discussed above. The substance insert mayalso comprise a FTD and a frame, each as described above. In somearrangements, the first and second materials for the flexible barrierare integrated into a single part, and they may comprise layers of amulti-layer flexible barrier. In some arrangements, the first materialis an adhesive.

Also provided is a substance compartment comprising a flange, and adrawn cavity having a proximal end which extends from the flange to adistal end. The distal end may accept a substance, while the proximalend is collapsible to form a frangible seal aseptically sealing thesubstance in the distal end of the cavity. The substance compartment mayalso comprise a FTD at least partially disposed in the distal end of thecavity.

Various methods are contemplated by the disclosure. One embodimentprovides a method for use with a packaged product such as describedabove. According to this method, the container is externally andaseptically manipulated to jeopardize the integrity of the flexiblebarrier, thereby forming a merged compartment within the container toallow merger of the first and second substances. The method may alsocomprise dispensing the merged contents through a FTD that is moved,either rotationally or otherwise, from a pre-dispensing position whereinthe FTD is separated from the merged compartment, into a dispensingposition wherein the FTD is in communication with the mergedcompartment. In other arrangements, the FTD is disposed at leastpartially within the container and the packaged product is externallyand aseptically manipulated by moving the substance insert away from ortoward the FTD, or by moving the container relative to the FTD. Duringexternal manipulation of the container, which may occur either manuallyor through an actuator, at least a portion of the substance insert movesin correspondence with the container. In some arrangements, the firstsubstance, the second substance, or both are pressed against theflexible barrier upon external manipulation of the container. Integrityof the flexible barrier may be jeopardized by movement of the productinsert in response to deformation of the container. The barrier can bejeopardized by separating a frangible seal, rupturing the barrier, orotherwise.

A method is also contemplated for manufacturing a packaged product.According to this method, (1) a container of a selected configuration isformed that comprises at least a first compartment for storing a firstsubstance; (2) a substance insert is formed which comprises a secondcompartment filled with a second substance; and (3) the substance insertis inserted at least partially into the container such that a flexibleand susceptible barrier is interposed between the first and secondcompartments. In this context, susceptibility of the barrier is intendedto mean that its integrity can be jeopardized in any of a variety ofmanners, such as by breaking a seal, rupturing the barrier, puncturingthe barrier, or otherwise. In some arrangements, the substance insert isformed to include a pouch with a FTD on one portion of the insert and afrangible seal on another portion of the insert. The pouch may besupported in a deformable or rigid frame. In another arrangement, thesubstance insert is formed as a blister pack.

Some embodiments provide a plurality of at least partially collapsiblesubstance inserts, each comprising a respective compartment that isfilled with a respective substance, with each of the substance insertsbeing inserted at least partially into the container. The firstcompartment may be interposed between the substance inserts. In otherembodiments, the container includes a plurality of containercompartments, each storing a respective substance, and the substanceinsert is interposed between the container compartments. Preferably, thecontainer is at least partially deformable and may be configured as asqueeze tube, a bottle or any other suitable configuration.

According to this method, the first substance may be introduced into thefirst compartment either prior to or after insertion of the substanceinsert. The FTD may also be inserted into the container. The method mayalso incorporate a Blow-Fill-Insert-Seal (BFIS) process whereby (1) atleast a portion of the container is blow molded to form the firstcompartment; (2) the first substance is introduced into the firstcompartment; (3) the substance insert is inserted into the container;(4) the first substance and the substance insert are aseptically sealedinside the container; and (5) the substance insert is interfaced with aninterior of the container in a fluid tight manner. A FTD may be eitherinserted partly into the container or formed in the container. Alsoaccording to this method, the container may be molded, with thesubstance insert introduced at least partially into an opening of thecontainer and interfaced in engagement with the container, preferably bysealing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 a-1 c demonstrate a first exemplary embodiment of a packagewhere the substance-insert is separated from the applicator insert;

FIGS. 2 a-2 c demonstrate another exemplary embodiment of a packagewhere the Substance-insert is a blister;

FIGS. 3 a-3 d demonstrate another exemplary embodiment where thesubstance-insert Is associated with the applicator-insert;

FIG. 3 e illustrates a syringe which employs the packages shown in FIGS.3 a-3 d;

FIGS. 4 a-4 e demonstrate a further exemplary embodiment where thesubstance-insert is included in the applicator-insert;

FIGS. 5 a-5 h demonstrates a further preferred embodiment where thesecond compartment is a film pouch associated with the applicatorinsert.

FIGS. 6 a-6 f demonstrate the details of one preferred fashion of makingthe film capsule for the embodiment of FIGS. 5 a-5 h;

FIGS. 7 a-7 c demonstrate a further preferred embodiment where theflexible barrier is jeopardized during application, rather than prior toit;

FIG. 8 a-8 b show general views of an exemplary package and theproduct-insert thereof;

FIGS. 9 a-9 f show several views of an exemplary embodiment of thesecond container for the packaged product;

FIGS. 10 a-10 c show a further exemplary embodiment of the secondcontainer;

FIGS. 11 a-11 g show views of an exemplary embodiment of theproduct-insert in the sealed and open states;

FIGS. 12 a-12 d show detailed views of an exemplary embodiment of thepackage in the sealed and opened states;

FIG. 13 shows the container of FIG. 8 in an in-use state;

FIGS. 14 a-14 b show an exemplary embodiment of the package where anexternal device facilitates the manipulation of the container to theopen state;

FIG. 15 shows a further exemplary embodiment of the package where aremovable section provides access to the fluid transport device andexposes a portion of the substance-insert;

FIG. 16 shows a further exemplary embodiment of the package where aportion of the substance-insert is exposed;

FIGS. 17 a-17 b show a further exemplary embodiment of the package wherethe container is in a form of a tube;

FIG. 18 shows an exemplary embodiment where the substance-insert isspaced apart distally from the fluid transport device;

FIG. 19 shows an exemplary embodiment where the substance-insert isreduced to a flange with a film valve;

FIG. 20 shows an exemplary embodiment where the substance-insert isreduced to a flange with an integral valve;

FIG. 21 shows an exemplary embodiment where the valve is integral to thecontainer;

FIG. 22 shows an exemplary embodiment where the substance-insertcomprises a filter;

FIG. 23 shows an exemplary embodiment where the first-compartment andthe second-compartment comprise a screw-cap port;

FIG. 24 shows an exemplary embodiment where the container is made from asleeved web;

FIG. 25 shows an exemplary embodiment where the package comprises twosubstance-inserts;

FIG. 26 shows an exemplary embodiment where the package comprises asubstance insert with two valves; and

FIGS. 27 a-27 c shows an exemplary embodiment where the web of the pouchof the second-compartment forms the first compartment.

DETAILED DESCRIPTION

Disclosed is a package in the form of a container comprising a firstcompartment containing a first substance, and a substance-insert atleast partly disposed in said container with said first substance. Thesubstance-insert comprises a second compartment containing a secondsubstance, and at least part of said compartment is made from flexiblebarrier wall. The package can be externally and aseptically manipulatedto mix the said first substance and said second substance prior todispensing, by jeopardizing the integrity of said film wall. Thearrangement allows the container to be semi rigid thus providing betterergonomics of the package. The film wall provides a good barrier betweenthe first substance and the second substance supporting longer shelflife and stability of the products.

The container can further comprise an insert comprising a fluidtransport device. The fluid transport device can be in the form of anapplicator for dispensing the content of the package in a desiredfashion to a desired target. Various applicator types may beincorporated with the container to suit a designated applicationincluding a spout, orifice, tube, hose, dripper, brush, sponge, nozzle,spray-head, hypodermic needle, a micro needle or micro needle array, aneedless injection orifice a canula a tube a combination of the above,or one or more of a connector, a passage, a facilitator, a valve, aseptum or a coupler to one or more of the above applicators. Thearrangement is such that when the integrity of the aseptically sealedcontainer is broken at the designated location the applicator is exposedand becomes available for use. + p In some embodiments thesubstance-insert and the applicator-insert are integrated as one insert,advantageously simplifying the manufacturing of the package. In otherembodiments manipulation of the container to open also causes the firstand second compartments to merge. In other embodiments the opening ofthe package is conditioned by first manipulating the compartments tomix. In yet other embodiments the merging of the compartments isconditioned by first manipulating the package to open.

The present invention is not limited to one substance-insert and isapplicable to multi compartments-inserts. Furthermore the package maycontain a plurality of first compartments that can be either utilizedseparately or merged.

The term dispensing generally refers to any form of expressing thecontent of the package and captures other terminology such asadministration, delivering, infusing, dripping, application, pouring,smearing, spreading, injection and other forms of introducing a productto a target location in a desired fashion.

The term flexible barrier and the term film generally refers tomono-layer films, multi-layer films, extruded films, blown films, rolledfilms, laminated films, metal foils, ceramic or oxide laminates, blowmolded, injection molded, cast, other forms of flexible barriers know inthe art of combination of the above.

In some preferred embodiments the second compartment is at least partlymade of film or foil and the integrity of the seal of the compartment isjeopardized (some times hereafter referred to as breached or opened) byeither: a) separating or peeling apart a frangible seal between at leasttwo wall of the second compartment, b) piercing at least one wall of thesecond compartment by a piercing object, c) or by breaking or rupturingat least one wall of the second compartment.

In some preferred embodiments the second compartment is completely madefrom high barrier film, advantageously providing a high barrier tomoisture and gas.

The second compartment is manipulated to open and establish fluidcommunication with the first compartment by external manipulation of thepackage in an aseptic fashion.

In some embodiments said second substance comprises a liquid, asolution, a gel, paste, compressed powder, loose powder, a solid orsolid particles, pellets, a lyophilized cake, emulsion, gas, orcombination of the above. In some embodiments the second substance is avaccine in a dry format and the first substance is a diluent and wheresaid vaccine has improved stability and extended shelf life when in dryformat, and where said diluent and dry powder vaccine are mixed toreconstitute prior to administration.

Administration can be in one of the forms commonly used in the art suchas injection, topically, orally, nasally, by inhalation or by any othermeans known in the art.

In some embodiments at least one of the first substance and the secondis pressurized by external manipulation of the container to cause theflexible barrier to be jeopardized to allow the first and secondsubstances to merge. The flexible barrier is supported around itssusceptible portion such that applied pressure to the flexible barrieris translated into applied force to the susceptible portion of theflexible barrier.

In some embodiments the interface of the substance insert with thecontainer is such that deformation of the container will translate intomovement of the substance insert. The interface supports the flexiblebarrier such that movement results in applied force to the susceptibleportion of the flexible barrier. Thus external deformation of thecontainer results in jeopardizing the flexible barrier allowing thefirst and the second substances to merge.

In some embodiments the package is made in a BFIS process. In otherembodiments the package is made in a FFS method. In some embodiments thefirst compartment (or compartments) is blow molded or injection moldedand the substance-insert (s) is introduced to the package prior, duringor post molding of the first compartment, or during or post forming ofthe first compartment.

The term substance is generally referred to a content of a filledcompartment prior to allowing it to merge with the other compartment orcompartments which form a product. A substance may be a pure or uniformsubstance or a combination of substances.

In the following detailed description, reference is made to theaccompanying drawings which form a part hereof, and in which is shown byway of illustrations specific embodiments for practicing the invention.The leading digit(s) of the reference numbers in the figures usuallycorrelate to the figure number, with the exception that identical orcommon components which appear in multiple figures may at times beidentified by the same reference numbers. The embodiments illustrated bythe figures are described in sufficient detail to enable those skilledin the art to practice the invention, and it is to be understood thatother embodiments may be utilized and changes may be made withoutdeparting from the spirit and scope of the present invention. Thefollowing detailed description is, therefore, not to be taken in alimiting sense, and the scope of the present invention is defined onlyby the appended claims.

In the description of the Figures the term front of a part, feature oran assembly refers to the side facing the application (or dispensing)end, and the term back of a part, assembly or feature is the sideextending away from the application side.

Referring first to FIGS. 1 a-1 c, a packaged product 100 is shown.Associated with package 100 is a container 110, in which a fluidtransport device insert in a form of an applicator (here after sometimesreferred to as “applicator-insert”) 113, and a substance-insert 112 areseparately included in fluid communication with a first compartment 119which is formed in said container. FIG. 1 a shows an exploded sidesection view of the package 100 where the substance-insert 112 is offsetfrom its actual position in the container 100. The applicator-insert 113is in the fashion of a dropper nozzle, and is aseptically protected fromthe environment by a twist-off portion 122 integrally formed in thecontainer 110. The twist-off portion 122 is connected to the container110 via a weakened section 123 which will break upon a sufficienttwisting action to expose the tip of the dropper nozzle 111 of theapplicator-insert 113. The package of FIG. 1 can be manufactured by aBFIS method. With slight design modifications similar packagings couldalso be manufactured by a process involving injection-insert-molding orby a process involving blow molding, or by a FFS process. Where themanufacturing method is BFS or BFIS the applicator insert can bereplaced by a similar feature directly formed in the container 110.Where the container 110 is manufactured by injection molding, theapplicator-insert 113 can be replaced with a similar feature directlyformed in the container 110, and the twist off portion 122 can beconnected to the container 110 by ultra-sonic welding or spin-welding orany applicable connection method known in the art. The substance-insert112 can be manufactured on a separate filling line. The applicatorinsert 113 can be one or more of a variety of fluid transport devicesknown in the art including, a topical applicator such as a brush,sponge, spatula or wiper; a spray-head, squirt-nozzle, a nasalapplicator, oral applicator, or ear applicator; an invasive applicatorsuch as a needle, a cannula, a soft cannula, a catheter, a tube or ahose; a connector such as a Luer Lock connector, a septum for receivinga needle or a hollow spike such as infusion set spike; other applicatorsknown in the art; or a coupler to one or more of the above. Thecontainer 110 can be manufactured from various materials known in theart including Polypropylene or Polyethylene.

The substance-insert 112 comprises a cylindrical barrel 118 in which aplunger 116 is disposed from the back end of said barrel 118. A flexiblebarrier in the form of a film portion 117 seals over the front end ofthe barrel 118, defining a second compartment 114 in the barrel 118between said film 117 and the front end of the plunger 116. The secondcompartment is filled with a second substance 115. The second substance115 can be in various forms including a liquid, emulsion, mixture,suspension, solution, gel, paste, solid such as compressed powder, loosepowder such as spray dried or grinded powder, lyophilized cake,granulated substance, pellets, pill, gas, or any other form known in theart or a combination of the above. The film portion 117 extends to wraparound the barrel 118 and connect to the back end of the plunger 116such that the isolation of the second substance from the environmentdoes not depend on the seal quality of the cylindrical mating betweenthe plunger 116 and the barrel 118. In other embodiments the flexiblebarrier 117 further extends to completely seal around the plunger 116thereby establishing an integral film package around thesubstance-insert 112 which improves the barrier properties around thesecond substance 115. In another embodiment the film portion 117 islimited to the front end of the barrel 118 which provides a tight sealto the front side of the second-compartment 114, and the seal of theback end of the second compartment is left to the seal between theplunger 116 and the barrel 118 such as a tight-fit seal. In reference tothe flexible barrier 117 the term film generally refers to films andfoils including monolayer films, multi-layer films, extruded films,blown-films, laminated films, metal foils, ceramic or oxide laminates,other types of membrane materials or any combination of the above. Theflexible barrier 117 can be attached to the rest of the substance-insert112 by various means including heat seal such (heat stake, hot-plate,ultrasonic, RF, IR) or by adhesion or by any other means known in theart. The film portion 117 comprise a collapsible section 125 thatinterconnects (bridges between) the back end of the barrel 118 and theback end of the plunger 116, allowing relative motion of the plunger 116into the barrel 118.

Referring now to FIG. 1 b, a side view with a broken-out section of thepackage 100 prior to activation is demonstrated. The substance-insert112 is accommodated in an extension of the first compartment 126 suchthat the product 112 is aseptically confined in the container 110; thefilm portion 117 separates between the first substance 119 in the firstcompartment 126 and the second substance 115 in the second compartment114. The extension of the first compartment 126 comprises a collapsibleportion 124 with a wall geometry similar to the collapsible portion 125of the film portion 117 of the substance-insert 112, providing theflexibility for manipulating the plunger 116 to move forward inside thebarrel 118. The first substance 119 can be in various forms including aliquid, emulsion, mixture, suspension, solution, gel, paste, solid suchas compressed powder, loose powder such as spray dried or grindedpowder, lyophilized cake, granulated substance, pellets, pill, gas, orany other form known in the art or a combination of the above. Theportion of the wall of the first compartment 126 that confines the firstsubstance 119 comprises a geometry of a bellows which allows forefficient expression of the first substance 119 therein when the firstcompartment 126 is forced to collapse. The barrel 118 provides aninterface to the container 110 which is undisturbed during ordinaryoperation of the container. The barrel further supports a susceptibleportion of the flexible barrier 117.

Referring now to FIG. 1 c the package 100 is demonstrated afteractivation. The plunger 116 is displaced forward by applying externalforce as the arrow indicates. Moving forward the plunger 116 causes thesecond substance 115 to press against the susceptible portion of theflexible barrier 117 in front of the barrel 118. As the susceptibleportion of the flexible barrier 117 is supported by the barrel 118 theapplied depression of the second substance 115 is translated to appliedforce on the susceptible portion causing it to rupture and establishfluid communication with the first substance 119, allowing the twosubstances to merge into a merged compartment. In another embodiment theextension of film portion 117 is limited to the front of the barrel 118and the seal between the barrel 118 and the film portion 117 is suchthat pressing the content 115 causes the flexible barrier 117 to peel(rather than rupture) and thereby establish fluid communication with thefirst fluid 119. When the plunger 116 is fully pushed forward the headof the plunger 116 is flush with the front of the barrel 118 and theback wall of the first compartment 126. In further activation steps thetwist-off portion 122 is removed, at which point a squeeze of the firstcompartment 126 by further application of force on the plunger 116 inthe direction of the arrow will cause the merged contents to expelthrough the applicator 113 (not shown).

In a further configuration the plunger 116 comprises a rupturable memberextending into the second compartment 114 and reaching proximately tothe susceptible portion 117 such that, as soon as the plunger 116 beginstraveling forward, the rupturing member will reach the film portion 117and facilitate the rupturing of the film 117. The rupturing member maybe merely a sharp spike extending from the plunger head.

In a further embodiment a rupturing member is movably disposed in thesecond compartment 114 along with the second substance 115 such that, assoon as the plunger 116 begins traveling forward, the rupturing memberwill rupture the susceptible portion of the flexible barrier 117.

In some embodiments the twist off portion 122 can be replaced to protectthe applicator for further uses. Where the applicator-insert is a sharpobject the twist off portion can be replaced to avoid accidental contactwith the sharp.

The package 100 provides a high level of ergonomics and a good contentexpress rate, while also providing isolation of the first substance 119from the second substance 115 through the high barrier film portion 117.

It will be apparent to those skilled in the art that the packagedproduct 100, as well as other packaged products and packaging describedor contemplated herein, can be packaged in a secondary package such as ashipping package, a pouch, a package that reduces or eliminated exposureto light or to other environmental effects, and so forth.

It will further be apparent to those skilled in the art that the packagecan be associated in a further device, an actuator or system whichfacilitates the use of the package, or in which the package anddispensing thereof is being utilized.

It will further be apparent to those skilled in the art that certainembodiments may comprise a plurality of packages or a plurality ofelements of the package combined with common elements of the packagecontainer. For example in one embodiment two first compartments eachassociated with a substance-insert may communicate with a commonapplicator-insert.

Referring now to FIGS. 2 a-2 c, a further exemplary package 200 isdemonstrated. Like in package 100 of FIG. 1 the substance-insert 212 isaccommodated in a backward extension of the first compartment 226. FIG.2 a demonstrates an exploded side view with a broken-out section wherethe product-insert 212 is offset backward from its actual location inthe container 210. The insert 212 is constructed of a flexible barriercomprising a first film wall 217 and a second film wall 221 which isformed to have a concave shape. The two films are connected along theirperimeters to form a sealed second compartment 214 in the form of ablister containing the second substance 215. The insert compartment canbe manufactured in a FFS line or by any other manufacturing method knownin the art and introduced to the container 210 during the formation ofthe container 210 or adjacent to the first substance (not shown) fillingstep. The joint perimeter of the blister defines an interface to thecontainer 210.

Referring now to FIG. 2 b. The substance-insert 212 is accommodated in apocket 229 at the back of the first compartment 226, such that the filmwall 217 separates the first substance 219 from the second substance215. The back wall 227 of the first compartment 226 has a dome shapethat can be pressed to collapsed toward the substance-insert 212.

Referring now to FIG. 2 c the package 200 is shown from a side view witha broken-out section, during the activation state. The back wall 227 hasbeen manipulated to collapse into the first compartment 226 by applyingforce in the direction of the arrow, forcing the second wall 221 of thesubstance-insert 212 to also collapse into the second compartment 214,thereby causing the second substance 215 to press against the first filmwall which is supported by the interface to the container. Thistranslates the applied press of the second product on the first filmwall 217 to applied force on the susceptible portion of the flexiblebarrier which causes it to rupture, allowing the first substance 215 andthe second substance 219 to merge. Various mechanisms can facilitate therupture of the first wall 217 of the substance-insert 212. In oneembodiment the first film 217 comprise a slit line along its center thatcauses stress concentration as the second substance is pushing againstfirst wall 217. The first wall 217 of the substance-insert 212 is shownruptured whereby fluid communication is established between the firstcompartment 226 and the second compartment 214 allowing the firstsubstance 219 and the second substance 215 to merge. Subsequentactivation steps include removing the twist-off portion 222 therebyexposing the applicator (not shown), associating the applicator with itstarget, and continuing to press on the back of the first compartment tocause the product to expel through the applicator. The first compartment226 has a bellows shape that allows for efficient express rationing ofthe content. The substance-insert 212 is mostly flat and flush with theback wall of the first compartment 226 such that it does not interferewith efficient expression of the content.

Referring now to FIGS. 3 a-3 e, a further preferred embodiment isdemonstrated. FIG. 3 a demonstrates a section view of package 300 at thepre-activation state. The substance insert 312 comprises a flexiblebarrier in a form of a film strip 333 which is folded over and sealedonto itself to form a second compartment 314 therein, leaving first anda second loose ends of the strip 334 and 335. The seal that formscompartment 314 is a frangible seal (sometimes referred to as peelableseal) that can be separated if the first and the second loose ends ofthe strip are pulled apart. The first end of the strip 333 is supportedby the the fluid transport device insert 313 (also referred to as(“applicator-insert”) in a form of an applicator, and the second end issupported by the plug 336. The applicator insert 313 comprises a needleassembly 331 comprising a needle 327 and a needle hub 329. Theapplicator-insert 313 further comprises a housing 332 in which theneedle assembly 331 is accommodated such that it can be made to movebackward along the longitudinal direction of the needle 331. Theapplicator-insert 312 further comprises a needle protector 337 having aproximal end attached to the housing 332 in an aseptically sealedfashion, and extending to provide a cover to the distal sharp end of theneedle assembly 331. The plug 336 comprises a cylindrical engagementinterface to the container which is connected in a fluid tight fashionto the back end of the container 310 and a grip portion extendingbackward from the seal portion to provide a convenient means foractivating the package 300, as will be detailed bellow. The container310 comprises a bellows having a front opening adapted to receive andengage with the housing 332 and a back opening adapted to receive theplug 336. The housing 332 of the applicator-insert 313 is accommodatedin the front opening of the container 310 and sealed to it in afluid-tight fashion. The plug 336 is accommodated in the back opening ofthe container 310 and sealed to it in a fluid tight fashion. The strip333 and the second compartment 314 formed therein are confined in thefirst compartment 326 such that the seal of the strip 333 to itselfconstitutes a separation between the first substance 319 and the secondsubstance 315.

Referring now to FIG. 3 b, the package 300 is demonstrated duringactivation. The grip of the plug 336 has been pulled in the direction ofthe arrow thereby causing the first compartment to elongate. As aconsequence the first end 334 of the strip 333 and the second end 335 ofthe strip are pulled apart causing the seal around the compartment 314to separate, establishing fluid communication between the firstcompartment 326 and the second compartment 314 thereby merging the firstand second substances into a merged compartment. In a further embodimentthe arrangement is such that the plug is twisted or rotated relative tothe housing 332, pulling the strip ends apart and separating thefrangible seal of the second compartment 314.

FIG. 3 c demonstrates the package 300 upon completion of the injection.The bellows is at the fully collapsed state leaving a minimal“dead-space” of unexpressed product. At this point the plug 336mechanically engages the needle hub 329. The film strip 333 is flexibleand thin enough so as not to present an obstacle for efficientexpression of the contents of the container 310 when squeezed.

FIG. 3 d shows the package 300 after the bellows has been restoredsubstantially to its original shape. The plug 336 remains engaged withthe needle hub 329 thereby pulling the needle assembly into thecontainer 310 and disabling the package from being reused such that thetip of the needle is protected from causing injuries or damage.

FIG. 3 e shows the package 300 accommodated in a device having a generalform of a syringe 340 comprising a barrel 342, an actuator 344 and aspring 346 disposed therebetween biasing the actuator out of the barrel.The package 300 is supported by the front wall 348 of the barrel. In theback, the plug 336 is engaged with the actuator 344. The device 340(which can also be considered a package) can ergonomically facilitatethe operation of the package 300 and in particular the stage ofreconstituting the original shape of the barrel in which the spring 346will force the actuator 344 out of the barrel 342 and pull the plugalong with it. The device can be part of a single use kit along with thepackage or can be used multiple times by replacing the package 300.

Referring now to FIGS. 4 a-4 e a further exemplary embodiment isdemonstrated where the applicator 413 is integrated with thesubstance-insert 412 (hereafter in this embodiment collectively referredto as the “substance insert”) and introduced to the rest of the package400 in the manufacturing process as one. FIG. 4 a demonstrates anexploded section view of the pre-activated state of the package 400. Thesubstance-insert 412 comprises a housing 432, a needle assembly 431movable within the housing 432 (comprising a distal sharp-end fordelivering the content of the package 400 to a subject, and a proximalsharp for piercing the housing 432 in order to establish fluidcommunication between the contents of the package 400 and the needle);and a needle protector 437 accommodated in the housing 432 and movablewithin the housing to manipulate the needle assembly 431 to displacebackward and pierce the housing 432. The substance insert furthercomprises a flexible barrier in a form of a tubular pouch compartmenthaving a proximal open end attached to the housing in a fluid tightfashion, and a distal end where the pouch seam is collapsed to seal toitself in a frangible seal fashion. The needle protector 437 providesprotection from accidental needle-sticks and/or aseptic conditions tothe needle assembly until the time of use

Referring now to FIG. 4 b, the substance-insert comprises a pouch 442formed from first and a second films attached to each other along theirperimeter, and attached to the housing 432 to form the secondcompartment 414, which contains the second substance 415. A portion ofthe attachment between the first film and the second film of the secondcompartment 414 has a weakened seal force defining a frangible seal(sometimes referred to as peelable seal) section 441. The insert isaccommodated at a neck section 444 in the front of the container 410.The housing provides an interface to the container 410 forming a firmfluid tight engagement. In one embodiment the neck portion 444 isfurther attached to the flexible barrier section 441 in a fluid tightfashion providing support to the susceptible portion of the flexiblebarrier, with the seal force between the flexible barrier and thecontainer being stronger than the frangible seal force of the flexiblebarrier to itself. The frangible seal section 441 defines a separationbetween the first substance 419 and the second substance 415.

Referring now to FIG. 4 c, the package 400 is demonstrated in theactivation process after the first compartment 426 and the secondcompartment 414 have been merged to allow the first substance 419 andthe second substance 415 to merge. Three preferred methods for causingthe two compartments (426, 414) to merge will be described:

-   -   a) In the first method the first compartment 426 is pressurized        by applying force to the bellows-shaped first compartment 426 in        the direction of the arrow. The neck of the container 410 is        attached to frangible seal section 441 in a fluid tight seal        fashion such that the pressure in the first compartment 426        biases the neck to expand, thereby pulling apart the first wall        and the second wall of the second compartment 414, resulting in        separation of the frangible seal and merger of the two        compartments and their contents.    -   b) In the second method the user pressurizes the second        compartment 414 by pinching the second compartment 414 through        deformation of the neck of the container 410, thereby        pressurizing the flowable second substance 415 which forces the        frangible seal 441 to separate and the first and second        compartments (426,414) to merge.    -   c) In the third method the neck of the container 410 is attached        to frangible seal 441 section. The elongated thinned area of the        neck where it is attached to the frangible seal 441 is        compressed by pressing the two distal ends of the section toward        one another causing them to collapse and arch away from each        other thereby causing the frangible seal 441 to separate.

FIG. 4 d demonstrates a subsequent step whereby the protector 437 ispushed back to cause the proximal sharp end of the needle assembly 431to penetrate the thin membrane at the back of the housing wall 434thereby establishing fluid communication with the contents of thepackage 400. The membrane of the housing 432 is preferably made from apolymeric material which is substantially resilient to allow penetrationof the back sharp end of the needle with hand force, and maintain afluid tight seal between the needle and the membrane.

FIG. 4 e shows the package 400 at the end of the delivery state. Theprotector is now removed and the bellows-shaped first compartment iscollapsed to cause substantially complete expression of the product.

Referring now to FIGS. 5 a-5 h a further preferred package 500 isdemonstrated where the applicator-insert 513 and the substance-insert512 are combined. FIG. 5 a provides a general perspective view of thepackage 500, showing the container having a bellows shapedfirst-compartment 526 on its back end, and a neck 544 for receiving andengaging with integrated insert 512/513. The insert comprises a needleprotector 537 having 4 ribs 539 extending radially outwardly base. Thefour ribs are hollow as will better demonstrated in subsequent figuresto accommodate reciprocal ribs at the needle hub 529. FIG. 5 bdemonstrates an exploded perspective view of the package 500 where theinsert housing 532 and the needle assembly 531 are displaced from theirposition in the container 510. The needle hub 529 comprises a throughhole for accepting the needle 527, four ribs extending 550 in a radialdirection to communicate with the four hollow ribs 539 in the container510, and a threaded portion 552 to communicate with reciprocal threadingin the insert housing.

FIG. 5 c demonstrates the integrated substance-insert 512/513. Theintegrated-insert 512/513 comprises a housing 554, the needle assembly531, and a second compartment 514 in a form of a blister-pack, made froma flexible barrier. The needle assembly 513 comprises (1) the needle 527having a distal sharp end for administrating the contents of the package500 to a subject and a proximal end for piercing the second compartmentand introducing the merged product to the needle 527; and (2) the needlehub 529 associated with the needle 527. The needle hub 529 isaccommodated in the housing 532 and is engaged to the housing via areciprocal thread on the internal wall of the housing and the externalside of the needle hub 529, such that when the needle hub is turned itadvances along the axis of rotation (mutual with the axis of theneedle). The substance insert 512 comprises a flexible barrier in a formof a film portion 517 formed and sealed to itself by a frangible seal555 to form a second compartment 514 filled with the second substance515. The film portion 517 is supportably attached to the back end of thehousing 532 along its perimeter 556. The housing is also referred to as“frame”. The insert can be manufactured on a separate manufacturing linethan the container and the integration of the package.

FIG. 5 d demonstrates a side section view of the package 500 in the restposition. The integrated insert is accommodated in the container 510 infront of the first compartment 526, such that the frangible seal 555 ofthe second compartment 514 constitutes a flexible barrier between thefirst substance 519 and the second substance 515. The container 510extends along the insert and forms a twist-off portion 522 around theneedle 527. The twist-off portion 522 comprises hollow ribs that areengaged with the reciprocal ribs in the needle-hub 529 such that whenthe twist-off portion 522 will be turned (form removal) the needleassembly will turn along with it. The package can be manufactured in aBFIS seal line. The housing's external surface provides an interface forengaging the container in a firm fluid tight fashion.

Referring to FIG. 5 e, the package 500 is demonstrated at a firstactivation step where the first and second compartments are merged tocreate a merged compartment 523. By squeezing the first compartment 526,in the direction of the arrow, the first substance 515 pressurizescausing the frangible seal of the second compartment 514 to separate,and for the two compartments to merge. Further squeezing of the firstcompartment 526 in the direction of the arrow causes the film portion517 to extend until it firmly leans against the partition wall in thehousing 532. The proximal sharp end of the needle assembly 531 isaccommodated in a through hole in the partition wall of the housing 532,such that the tip of the needle is confined in said hole preventing itfrom piercing the film portion 517.

Referring now to FIG. 5 f, the package 500 is demonstrated in asubsequent activation step. The twist-off portion 522 has been turned asthe arrow indicates causing it to disengage from the rest of thecontainer 510. The turning of the twist-off portion 522 caused theneedle assembly 531 to turn and retract toward the merged compartment byway of threads 552, causing the proximal end of the needle 527 toproject out from the partition wall of the housing 532 and pierce thefilm portion 517, thereby establishing fluid communication between thecontents of the package 500 and the needle 527. In one embodiment theintegrated insert is equipped with a seal that facilitates the fluidtight seal between the needle assembly 531 and the merged compartment.

Referring now to FIG. 5 g, the package 500 is demonstrated at asubsequent activation step in which the twist off portion 522 isremoved.

FIG. 5 h demonstrates the package 500 during administration of thecontents. A concaved section 553 in the back of the first compartment526 is made to fit into the film portion 517 as the first compartment526 is squeezed, thereby improving the express ratio of the package. Itwill be obvious to those skilled in the art that an alternativeactivation sequence may be applied, whereby, after stage 5 f, the bellowis released allowing the film portion 517 to relax and displace awayfrom the needle. Thereafter the protector is twisted-off therebyretracting the needle into the container. The package may then besqueezed to pressurize the product and cause the flexible barrier toextend toward the back sharp of the needle and cause it to rupture.

Referring now to FIGS. 6 a-6 f, a preferred design and method ofmanufacturing a second compartment 514 is demonstrated. FIGS. 6 a, 6 b,and 6 c demonstrate different views of the flexible barrier in a fashionof a film portion 517 after it has been processed to have a flangeportion 662 and a deep drawn cavity 661, having a proximal end proximalto the flange and a distal end. The pocket can be drawn bythermoforming, plug-assist forming, cold forming, or the part can beformed by blow molding, injection-molding, injection-blow-molding,blow-injection-molding, or other applicable molding or formingtechnologies known in the art. The second substance (not shown) isfilled to the cavity at that stage. FIGS. 6 d, 6 e, and 6 f demonstratedifferent views of the film portion 517 after the deep pocket 661 hasbeen sealed across 663 to form the compartment 514. The proximal end ofthe cavity is made to collapse and seal to itself to form the secondcompartment at the distal end of the cavity. The sealing can beperformed by various techniques including, heat-stake-welding, RFwelding, vibration welding, ultrasonic welding, laser welding, bonding,gluing or any other techniques known in the art for forming a frangibleseal. The seal 663 is a frangible seal that will be separated under thepresence of pressure at either side of the film 617 (i.e. the first orsecond compartments). The advantage of this design that it provides asmooth and flat flange portion 662 for connecting the film portion tothe housing (532 in FIG. 5) in a fluid tight seal fashion. In a furtherembodiment a fluid transport device is associated with the distal end ofthe cavity.

While the embodiments in the figures above are demonstrated with asemi-rigid container it will be apparent to those skilled in the artthat the approaches disclosed herein are applicable and advantageous inapplications where the container or the first compartment are rigid suchas a glass container, or flexible such as a bag.

FIGS. 7 a-7 c demonstrate another exemplary embodiment of a package 700.The substance insert 712 includes the applicator (or fluid transportdevice) 713 and comprises a housing 732 (which may be considered a framein this and the previous figures), a needle 727 attached to saidhousing, and a second compartment 714 for storing the second substance715. The second compartment comprises a barrel 718 and a flexiblebarrier 717 sealing the two open ends of said barrel 718. Portions ofsaid flexible barrier are supported by the barrel to define susceptibleportions of the flexible barrier at the two ends of the barrel.

The insert housing provides an interface to the container 710. Thecontainer comprises a distal end shaped as a bellows to form the firstcompartment 726, and a neck 744 (FIG. 7 b) that extends beyond theinsert to form a twist off portion 722 in a form of a needle protector737.

FIG. 7 b shows the package 700 after the needle protector 737 has beenremoved.

Referring now to FIG. 7 c, when the bellows is depressed the firstproduct 719 and the second product 715 press on the susceptible portionsof the flexible barrier 717. The support of the barrel 718 to theflexible barrier 717 translates the applied press on the flexiblebarrier to applied force on the susceptible sections of the flexiblebarrier causing them to rupture and permit the first and secondsubstances to merge and be dispensed.

Other package embodiments will now be described with reference to FIGS.8 through 27. Disclosed in these Figures (as above) are packageconstructs comprising a container for storing a first substance and atleast one substance-insert for storing a second substance at leastpartially disposed within said container. The product-insert comprises acontainer interface for engaging said substance-insert with thecontainer. The container comprises a first compartment for storing thefirst substance and the insert comprises a second compartment forstoring the second substance. The second compartment comprises aflexible barrier separating between the first and second substances, andhaving a susceptible portion that is supported in a way that translatesapplied pressure to the flexible barrier or certain deformation to thepackage into applied force to the susceptible portion of the flexiblebarrier, which in return jeopardizes the integrity of the flexiblebarrier and allows the substances to merge. When the flexible barrier isjeopardized the package is sometimes referred to hereafter as open oractivated. Before breaking the integrity of the flexible barrier thepackage is sometimes hereafter referred to as sealed or pre-used. Thesusceptible portion of the flexible barrier is sometimes referred tohereafter as a “valve” having an “open” and “closed” states.

In some of the remaining embodiments (as above) the substance-insertfurther comprises a frame for supporting the second container. The framefacilitates the introduction of the substance-insert to the containerduring manufacture. In some arrangements the frame provides the supportto the susceptible portion of the flexible barrier. In some arrangementsthe frame provides the container interface. The package is made suchthat certain deformation of the container, caused by externalmanipulation of the package, will jeopardize the integrity of theflexible barrier and allow the first substance and the second substanceto merge. In some arrangements the frame is substantially resilient tocorrespond to applied deformation to the package by correspondingdeformation to the frame which results in an applied force to thesusceptible portion of the flexible barrier which jeopardize theintegrity of the flexible barrier. In some arrangements the frame issubstantially rigid to support the susceptible portion such that, whenpressure is applied to the flexible barrier (due to deformation of thecontainer), it is translated to an applied force to the susceptibleportion, jeopardizing the integrity of the barrier.

In some arrangements the package further comprises a fluid transportdevice for delivering the merged contents of the package to a targetlocation in a desired fashion after the substances were allowed tomerge. In some arrangements at least a portion of the fluid transportdevice is formed in the container. In some arrangements at least aportion of the fluid transport device is formed in the substance insert.In some arrangements at least a portion of the fluid transport device isformed in the frame. In some embodiments at least a portion of the fluidtransport device is formed in the second compartment. In someembodiments at least a portion of the fluid transport device is aninsert associated with at least one of the container, product-insert,second compartment, and the frame.

In some arrangements the product-insert comprises more than onecompartment. In a preferred embodiment of the container, a least aportion of this compartment is a flexible barrier made from a film or afoil (hereafter sometimes referred to together as “web”). The web issealed around its edges to form a wall of said compartment, and at leasta portion of said seal is a frangible seal which can be separated underthe presence of sufficient peeling stress and serves as a single-usevalve. The web extends beyond the frangible seal sections to form aflange shaped membrane, which is arranged such that it will deliverforce to the frangible seal in the presence of pressure or particulardeformation of the container, and jeopardize the integrity of theflexible barrier. In some arrangements a frame is associated with theflange and provides the necessary support such that the pressure in thecontainer or the deformation of the container will be transferred to theflange in the appropriate way to cause the flange to open.

In some arrangements at least one of the compartments of the containeris pre-filled with a substance. In some arrangements at least onecompartment is filled at a later stage. In some arrangements thesubstances of at least two compartments are merged to form a product.Applications for the mixing containers include drug compounding, vaccinereconstitution, beverage or food preparation, lab applications, samplepreparation, adhesives, cosmetics, etc.

In some applications the container is used in an analytical process inwhich one of the compartments contains an instrument for measuring aproperty of a sample, which instrument may be a compound or probe. Insome applications the instrument is introduced through a port to thecompartment.

In some arrangements the area of the container extending from thecontainer interface and away from the first compartment forms a thirdcompartment substantially encapsulating the second compartment. Thethird compartment provides a mean for creating a desired controlledenvironment around the second compartment and substantially isolates itfrom the surrounding environment or the environment of the firstcompartment. In some arrangements a drying agent such as a desiccant indisposed in the third compartment to maintain a dry environmentsubstantially surrounding the second compartment. This is of aparticular advantage where the second product is a dry substance such asa food or pharmaceutical substance which perish or loose potency due tohumidity. In another arrangements the third compartment contains inertgas or liquid, or a thermally isolating filler. In some arrangementssaid third compartment accommodates a label such that the label can notseparate from the package, and is less exposed to weathering or physicaldamage.

Methods are also described or otherwise contemplated for manufacturingmulti-compartment containers using a Blow-Fill-Seal technology.

FIG. 8 a shows a package in the form of a hermetically sealed container810 having a general shape of a bottle. The container 810 comprises afluid transport device in the form of a closure 811 at one end forpouring the content of the container or introducing a substance into thecontainer 810. The container can be made from different materialsincluding thermoplastics such as Polypropylene (PP) or Polyethylene (PE)or a composition of several materials such as a multilayer plastic thatincludes Polyethylene or PVC layers, and EVOH layer to provide higherbarrier to moisture or oxygen transmission.

The container 810 can be made by several technologies includinginjection molding, gas-assist-injection-molding, injection-blow-molding,blow-molding, blow-fill-seal technology, vacuum forming, form-fill-seal,extrusion or sleeve forming, or any combination of the above. Thecontainer 810 holds a first substance in first compartment.

FIG. 8 b shows an exploded view of the container 810 revealing asubstance-insert 812 which is accommodated in the neck-portion 815 ofthe container 810. The substance-insert 812 comprises a 2nd compartment814 and a frame 813. The 2nd compartment is made to store a 2ndsubstance separately from the 1st substance. As will be demonstrated inthe following Figures, the 1st substance and the second substance can bemixed by external manipulation of the container without breaching theintegrity of the aseptic seal of the container 810.

FIG. 9 shows different views of the second compartment 814. FIG. 9 ashows a general view of the 2nd compartment 814. The second compartment814 comprises a flexible barrier in a form of a pouch 921 made from afilm or a foil (each and together sometimes referred to as “web”). Thepouch can be formed by several processes including: a) two flat orformed pieces of web sealed together along a sealing line, b) a singlepiece of web, flat or formed, folded and sealed along a sealing line c)an extruded or blown web sleeve flattened and sealed along a sealingcontour. A fitment 922 is accommodated between the two layers of filmthat form the pouch 921 providing a portion of the fluid transportdevice in a form of a port 923 to the 2nd compartment 814. A frangibleseal 924 seals along an edge of the pouch 814, defining a susceptibleportion of the flexible barrier, and the margin of the web beyond thefrangible seal 924 is formed into a form of a flange 925. The web can bemade from several materials including mono layer film such as PVC, PP orPE, a multi layer film such as PE/PCTFE for high oxygen and moisturebarrier; or foils such as AL/EVA. The pouch 921 further comprises alabel 928 or directly printed material.

FIG. 9 b shows an exploded view of the second compartment 814. Thefitment 922 confines a septum valve 926 for introducing a sharp objectsuch as a gauge needle or an infusion set spike to the secondcompartment 814 in a fluid tight manner. The septum 926 is topped with afoil portion 927 that maintains a high barrier integrity to the secondcompartment 814 as rubber septums suffer from relatively high moistureand oxygen transmission. The fitment 922 is made from a material thathas good compatibility for welding to the pouch's web, or compatible tothe adhesive that seals the fitment 922 to the pouch's web. In someembodiments the fitment provides other types of ports to the 2ndcompartment 814 including a spout for a replaceable threaded cap, asnapped on cap, or single use tear-off or twist-off caps, a Luer orLuer-Lock connector, other type of connectors, a needle, a dropletnozzle, a spray or mist nozzle, a topical applicator, or a hose or atube leading to one of the above ports.

FIG. 9 c shows a general view of the second compartment 814 from adifferent angle. The frangible seal 924 shows as a sealing line mark 930on the flange 925. The frangible seal is such that it would separate ata predefined separation tension (i.e. applied force). The frangible seal924 is such that a pull-off force between the one side web of the seal924 and the second side web of the seal will cause it to separate andinfringe the integrity of the pouch 921 establishing fluid communicationwith the external side of the flange. The pull-off force on the walls ofthe frangible seal can be created by a) fluid pressure in secondcompartment 814, b) matter pushing from the interior of the container814 against the frangible seal, c) fluid pressure presented at theexternal side 931 of the flange 925, d) matter pushing from the externalside 931 of the flange 925 against the flange 925 and/or the frangibleseal 924, or e) merely a pull apart force on the fringes of the flange925 (as is done in the practice of opening a snack pouch). In thismanner the susceptible portion of the flexible barrier in the form of afrangible seal acts as a single-use valve and will hereafter sometimesbe referred to as a “valve”.

FIG. 9 d shows the second compartment 814 after the frangible seal 924has been separated (i.e. valve opened), establishing fluid communicationbetween the 2nd substance and the external side 931 of the flange 925.The following figures will demonstrate that by opening the valve thefirst compartment and the second compartment merge, and the secondsubstance is allowed to merge with the first substance in the firstcompartment.

FIG. 9 e shows a front view of the second compartment to provideorientation of the section view of FIG. 9 f.

FIG. 9 f shows a section view of the second compartment 814 revealingthe 2nd substance 929 confined between the pouch walls 921, the fitment922, and the frangible seal 924. The 2nd substance 929 can be onesubstance or a combination of substances in various forms including gas,liquid, solution, suspension, gel, paste, loose powder, compressedpowder, pellets, granules, solid, or a combination of the above. In somepreferred embodiments the 2nd substance 929 is a pharmaceuticalingredient or vaccine in a dry powder form.

FIG. 10 demonstrates a different configuration of the second compartment1031.

FIG. 10 a shows a general view of the second compartment 1031. A portionof the fluid transport device in the form of a fitment 1034 comprises aflange 1035 that is attached to the external side of the pouch 1032 suchthat the fitment 1034 and the septum 1026 do not come in contact withthe 2nd substance 1029 until the time of use. The pouch 1032 is made byfolding a continuous web piece such that the area where the fitment 1034is attached is flat and clean of any seam lines.

FIG. 10 b shows a front view of the second compartment 1031 providingorientation of The section view in FIG. 10 c.

FIG. 10 c shows a section view of the second compartment 1031 showinghow the pouch 1032 provides a seamless surface 1033 for attaching theflange 1035 of the fitment 1034. A needle or a spike introduced to thecontainer 1031 through the septum 1026 will pierce the portion of thewall 1033 and establish fluid communication with the 2nd substance 1029.

FIG. 11 a shows the second compartment 814 associated with the frame813, together forming the substance-insert 812. A desiccant capsule 1118is associated with the frame.

FIG. 11 b shows an exploded view illustrating how the second compartmentis introduced to the frame. The flange 925 of the pouch 921 sealsagainst the flange 1141 of the frame 813. The fitment 922 isaccommodated at an opening 1142 of the frame 813. The frame 813 providesthe second compartment a rigid structure that facilitates theintroduction and accommodation of the substance insert 812 in the firstcontainer. The frame further provides support to the susceptible portionof the flexible barrier to facilitate the opening of the frangible seal924 as will be described below.

FIG. 11 c shows a general view of the substance insert 812 before thefrangible seal is separated. The flange 1141 of the frame 813 has theform of an oval or elliptical ring such that when the points on themajor axis of the ring 1143′ and 1143″ are displaced toward each other(or the center) the areas of the ring closer to the minor axis 1144′ and1144″ are displaced away from each other thereby pulling-off the wallsof the pouch 921 at the flange 925 area, causing the frangible seal 924to separate. Where substance is pushing against the external side 931 ofthe flange 925 the frame firmly holds the fringe of the flange andfacilitates concentration of the force on the flange 925 to separate thefrangible seal 924.

FIG. 11 d shows the substance insert 812 when the areas of the flange1141 of the frame 813, along the major axis ends 1144′ and 1144″ aredeformed toward each other, causing the frangible seal 924 to separate,opening the valve to the second container 814. A label 1145 can beaccommodated on the frame. Information can also be printed or otherwiseapplied directly to the frame.

FIG. 11 e shows the substance insert 812 when it is not deformed,providing orientation for the section view of FIG. 11 g.

FIG. 11 f shows the insert when the flange 1141 is deformed along themajor axis by applying force in the direction of the arrows 1146′ and1146″ at areas 1143′ and 1143″ of the flange 1141, to cause the valve toopen. It should be apparent to those skilled in the art that nothing inthe description above of the substance insert 812 is limiting to aparticular shape, form, or size, and that the substance insert 812 canbe designed to fit different container forms and applications. The frameof this particular embodiment can be made from a semi-rigid plastic withor without the support of metal elements that can improve its behavior.

FIG. 11 g shows a section view of the substance insert 812 to depict howthe second compartment 814 is accommodated in the frame 813 and how thesusceptible portion of the flexible barrier is being supported by theframe.

FIG. 12 a shows the container of an exemplary embodiment of the packageof the in a non-deformed state. FIG. 12 a provides orientation for thesection view of FIG. 12 b. The 1st container 810 is made by ablow-fill-insert-seal process (BFIS). Blow-Fill-Seal (BFS) technologyrefers to the manufacturing technique used to produce liquid filledcontainers and is considered to be the superior form of asepticprocessing in the packaging of pharmaceutical and healthcare products.The basic concept of Blow-Fill-Seal (BFS) is that a container is formed,filled, and sealed in a continuous process without human intervention,in a sterile enclosed area inside a machine. Thus this technology can beused to aseptically manufacture sterile pharmaceutical liquid dosageforms. The process is multi-stepped. Firstly, pharmaceutical-gradeplastic resin is vertically heat extruded through a circular throat, toform a hanging tube called the Parison. This extruded tube is thenenclosed within a two-part mold, and the tube is cut above the mold. Themold is transferred to the filling zone, or sterile filling space wherefilling needles mandrels are lowered and used to inflate the plastic toform the container within the mold. Following the formation of thecontainer, the mandrel is used to fill the container with liquid. Afterfilling the mandrels are retracted and a secondary top mold seals thecontainer. All actions take place inside a sterile shrouded chamberinside the machine. The product is then discharged to a non-sterilearea. Blow fill seal technology reduces personnel intervention making ita more robust method for the aseptic preparation of sterilepharmaceuticals. Generally the BFS plastic containers are made up ofpolyethylene and polypropylene. A slight variation to the BFS process iscalled Blow-Fill-Insert-Seal (BFIS) in which after the liquid filling aninsert is introduced to the container, before the secondary top moldseals the container. Typical inserts include rubber septums, connectors,and needles, and one manufacturer of such products is RommelagKunstsoff-Maschinen Vertriebsgesellschaft mbH from Waiblingen, Germany.

FIG. 12 b shows a section view of the package 810 of FIG. 12 a. Thefirst substance 1251 fills a portion of the container's firstcompartment. The first substance 1251 can be a single substance or acombination of several substances in various forms including gas,liquid, suspension, gel, past, loose powder, compressed powder, pellets,granules, solid, or any combination of the above. The substance insert812 is accommodated at the neck portion 815 of the container 810, suchthat the port 1142 is aligned with a tear-off closure 811 of thecontainer 810. The external face of the flange 1141 provides a containerinterface. Flange 1141 of frame 813 seals in a fluid tight fashionagainst the wall of the container 810 such that a third compartment 1252is formed which is free of the first substance 1251 or the secondsubstance 929, such that the first substance 1251 cannot reach the areaaround the pouch 814. The pouch's flange 925 separates between the firstsubstance 929 and the second substance 1251 in a fluid tight fashion. Insome embodiment a desiccant capsule (1118 in FIG. 11 a) is introduced inthe third compartment 1252 to reduce moisture that could transmit intothe second compartment 814.

FIG. 12 c shows the 1st container 810 when it is deformed in thedirection shown by the arrows 1146′ and 11465″ in the neck section 815,which in returns deforms the flange (1141 in FIG. 11) causing theopening of the second compartment 814 (opening of the valve) asdemonstrated in FIG. 11.

FIG. 12 c provides orientation for the section view of FIG. 12 d.

FIG. 12 d shows a section view of the 1st container 810 after the valveof the second compartment 814 has been opened and the 2nd substance 929(not shown) was allowed to merge with the first substance 1251 (notshown) creating the product 1253. A process for introducing a firstsubstance with a second substance without jeopardizing the asepticintegrity of the container 810 is thus demonstrated.

The third compartment 1252 can accommodate labels or printinginformation which is internal to the container 810, but is separatedfrom the first substance 1251 or the second substance 929 or theirproduct 1253, and is visible through the clear or semi-clear wall of thecontainer 810. This creates a unique opportunity to incorporate labelsin a protected fashion which can prevents label from being weathered,damaged, misplaced or replaced.

In one embodiment the package is an IV infusion bottle wherein the firstsubstance is water for injection (hereafter as commonly referred to inthe art “WFO”) and the second substance is a pharmaceutical in athermostable dry-powder form (such as insulin, antibiotic, interferon,biologics such as imiglucerase, and oncology drugs such as gemcitabine)which are mixed to create an infusion solution prior to administrationto a patient.

In one embodiment the package is a vaccine bottle where the firstsubstance is WFO and the 2nd substance is a vaccine in a thermostablepowder form where the first and second substances are mixed just priorto use and the product is drawn with a needle to a syringe and theninjected with the syringe to the patient.

In one embodiment the first substance and the second substance arehormones that should be combined just prior to a treatment.

In one embodiment the product 1253 is a beverage and the secondsubstance 929 is an additive such as a vitamin that is added to thebeverage 1251 just prior to consumption.

In one embodiment the product 1253 is a baby formula where the firstsubstance is water and the second substance is a baby formula powder.

In one embodiment the container is at least part of an analytical systemwhere at least one of the compartments of the package is associated witha probe or a measuring element that provides an indication of theproduct.

FIG. 13 shows the package of FIG. 12 ready for use. The closure (811 inFIG. 1) has been removed by a twist off action, and the foil protection(927 in FIG. 9 b) has been peeled off, and the fitment 922 is now readyto accept a spike of an infusion tube set. The package is placed withthe outlet port 923 pointing down and the product 1253 will flow out bythe suction force from the tube set (either forced pumping or gravity).The container walls will collapse inward to compensate for the depletingproduct 1253. In a further embodiment the container 810 can be piercedto allow air to compensate for the depleting content 1253. It will beapparent to those skilled in the art that other methods of introducingair into the container 810 are possible including ports with membranesthat prevent bacteria from penetrating the container 810.

FIG. 14 shows a preferred embodiment where an oval actuator ring orannulus 1471 is mounted on the neck 815 of the container 810. The ringserves to facilitate deformation of the neck 815 of the container 810 tocause the valve to open and the mixing action described in previousFigures. FIG. 14 a shows the pre-activation position where the majoraxis of the ring 1471—between points 1472′ and 1472″—is aligned with themajor axis of the neck 815—between points 1473′ and 1473″—whichrepresent the major axis of the frame's flange (1143′ and 1143″ FIG. 11f). FIG. 14 b shows the mixing position of the package where the ring1471 is turned a quarter turn such that its minor axis span betweenpoints 1474′ and 1474″ forcing the major axis points of the container'sneck 1473′ and 1473″ toward the center and the container to deform,causing the mixing action described in former Figures. It will beapparent to those skilled in the art that other external devices can beimplemented to facilitate the manipulation of the container to the openstate.

FIG. 15 shows a further preferred embodiment in which the twist-offclosure 1581 of the container 1580 extends substantially toward theflange to the root of the neck section 1515, such that after opening asignificant portion of the substance insert 1512 is exposed. In oneembodiment the removable portion 1581 is an opaque cap to protect thesecond substance (such as 929 in FIG. 9 f) in the product-insert 1512from exposure to light, and the pouch 1521 is clear to allow visualinspection of the contents after the removal of the removable portion1581. In one embodiment the twist-off removal action of the removablesection 1581 deforms the container 1580 in a similar manner that theoval ring 1471 does in FIG. 14 b thus causing the mixing action of thefirst substance and the second substance. In one embodiment theremovable section 1581 is rigid such that the deformation of the framefor the mixing action can only be performed after the removal of theremovable section 1581, providing a means for preventing accidentalmixing.

FIG. 16 shows a preferred embodiment of a package where the substanceinsert is partially inserted into the container. The container can bemade using a blow-molding, injection-molding, vacuum forming, filmsleeving or other processes known in the art, and the substance insert1612 is introduced to the opening of the container 1690 during, or afterthe walls of the container 1690 has been formed.

FIG. 17 shows a preferred embodiment where the container 1700 is in theform of a tube. Referring to FIG. 17 a, the walls of the container 1701are commonly produced by injection molding, and the open end of the tube1701 is sealed after the insert 1712 and the first substance 1751 havebeen introduced into the tube 1701. Referring to FIG. 17 b, the flange1741 is sealed against the tube wall 1701 by one or more of thetechniques know in the art including heat welding and/or press-fit.

FIG. 18 shows a further preferred embodiment where the substance insert1812 is accommodated in the container 1810 remotely from the fluidtransport device which is implemented in the first compartment.

FIG. 19 shows a further preferred embodiment where the substance insert1912 is reduced to an oval flange 1941, comprising a container interfacewhich is supporting a film barrier 1921 that has a frangible seal 1924on one end and it expands into a flange shape 1925 on the other end. Thesubstance insert 1912 forms a susceptible barrier between the firstsubstance and second substance that are confined directly in the firstcontainer walls 1922. The frangible seal will rupture when the container1920 is deformed in a similar fashion described in former Figures.

FIG. 20 shows a further embodiment where the insert is reduced to aflexible barrier that divides the container 2030 into a firstcompartment for the first substance 2051 and a second compartment forthe second substance 2029. The insert comprises a flange 41, comprisinga container interface that seals against the walls 2031 of the container2030 and a membrane 2032 extends inwardly to form the barrier and issupported by the walls of the container. A notch (score) 2033 is locatedon the membrane 2032 and will rupture when the container is deformed.The insert can be made from various materials including molded plasticsor sheet metal.

FIG. 21 shows a further preferred embodiment where the rupturableseparation 2142 is integrally molded with the walls 2141 of container2140. A notch 2143 in the separation causes the separation 2142 torupture when the container 2140 is deformed.

FIG. 22 shows an embodiment similar to embodiment of FIG. 17 with theexception that the substance insert 2212 includes a filter membrane 2252that covers the external side of the flange 2227. The filter 2252 allowsmixing of the first substance 2251 with the second substance 2229 butprevents larger objects (such as solid particles, suspended particles,large molecules or live cells) from penetrating from one substance tothe other substance. In one embodiment the filter 2252 is asemi-permeable membrane that prevents gas or liquid phase fromtransporting across the membrane. In one embodiment the filter is anactive membrane that causes chemical or physical separation of matter.In a further embodiment one of the compartments contains an analyticalinstrument and the membrane allows for specific materials to cross andreach said instrument.

FIG. 23 demonstrates a further preferred embodiment of a package wherethe container 2360 comprises replaceable screw-cap 2362 for the firstcompartment 2364, and a replaceable screw-cap 2363 for the secondcompartment 2365. The caps allows for filling the substances duringmanufacture or by the user, adding matter (such as additives, reagents,samples, etc.) to the substances or to remove the first or the secondsubstances or the product. In a further embodiment the caps are used tointroduce, observe, or remove an analytical or diagnostic instrument. Itwill be apparent to those skilled in the art that various type of portsknown in the art can be implemented in place of the screw-caps, and anynumber of ports can be implemented with the first and the secondcontainer.

FIG. 24 shows an embodiment where the container is made from a websleeve 2471. A tear-off notch 2472 facilitates the removal of the endportion 2473 to allow the user to reach the product. The flange of theframe is accommodated in the sleeve and its container interface is heatsealed to the sleeve 2471 after insertion at the welding area 2473.

FIG. 25 shows an embodiment with a second insert such that the container2580 can hold three substances. Fluid communication is establishedbetween the first compartment 2581 and the second compartment 2582, andthe first compartment 2581 with the third substance compartment 2583 inthe same fashion described in the context of FIG. 12. It would beapparent to those skilled in the art that any number of inserts can beintroduced in series or in parallel in the container.

FIG. 26 shows an embodiment of a package where the container 2690contains a substance insert 2612 with valves on the first end and on thesecond end. The first valve 2692 separates the second substance 2629from the first substance 2695, and the second valve 2693 separates thesecond substance 2629 from the third substance 2694. The valves areoperated by similar means as the valves of the former figures. It willbe apparent to those skilled in the art that the substance insert 2612may include any number of valves, and that any number of such insertsmay be included in the packaged product.

Referring now to FIG. 27, another embodiment of a package is shown.Referring to FIG. 27 a, the web 2701 forms the second compartment 2702as in FIG. 11 and it extends beyond the flange section to provide thewalls of the first compartment 2703. The frame 2713 is attached to thefirst compartment and supports the second compartment 2702 as in FIG.12.

FIG. 27 b provides orientation for section view 27 c.

FIG. 27 c shows how the web 2701 forms the second compartment 2702 andextends beyond the flange 2725 to form the first compartment 2703.

It will be evident to those skilled in the art that the invention is notlimited to the details of the foregoing illustrative embodiments andthat the present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof. Thepresent embodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

1. A packaged product, comprising: a. at least one container storing afirst substance; and b. at least one substance insert at least partiallydisposed within said container and storing a second substance, at leasta portion of said substance insert comprising a flexible barrier betweensaid first and second substances such that, when integrity of saidflexible barrier is jeopardized upon external manipulation of saidpackaged product, said first substance is permitted to merge with saidsecond substance.
 2. A packaged product according to claim 1 whereinsaid first container comprises a first compartment for storing saidfirst substance and said substance insert comprises a second compartmentfor storing said second substance, said second compartment comprisingsaid flexible barrier.
 3. A packaged product according to claim 2wherein said container comprises at least a third compartment storing athird substance to be merged with one or both of said first and secondsubstances.
 4. A packaged product according to claim 3 wherein saidthird compartment substantially encapsulates said second compartment tosurround the second compartment with a desired environment.
 5. Apackaged product according to claim 3 wherein said third compartment isseparated from the first compartment by a substance insert interface. 6.A packaged product according to claim 3 comprising a label disposed onsaid third compartment.
 7. A packaged product according to claim 4comprising a desiccant in said third compartment.
 8. A packaged productaccording to claim 2 wherein said substance insert comprises a framesupporting said second compartment.
 9. A packaged product according toclaim 1 wherein said flexible barrier comprises a frangible seal.
 10. Apackaged product according to claim 1 wherein said flexible barrier isrupturable.
 11. A packaged product according to claim 1 wherein saidsubstance insert comprises a frame.
 12. A packaged product according toclaim 11 where said frame is rigid.
 13. A packaged product according toclaim 11 where said frame is semi-rigid.
 14. A packaged productaccording to claim 11 wherein said frame supports a susceptible portionof said flexible barrier to translate a deformation of said containerinto a resulting force on said flexible barrier.
 15. A packaged productaccording to claim 11 wherein said frame supports a susceptible portionof said flexible barrier to translate pressure applied to said flexiblebarrier into an applied forced on the susceptible portion.
 16. Apackaged product according to claim 8 wherein said frame is a deformablemember attached to said flexible barrier such that deformation of saidframe translates into movement of said second compartment which breakssaid flexible barrier and permits said first and second substances tomerge.
 17. A packaged product according to claim 16 where said movementbreaks a frangible seal.
 18. A packaged product according to claim 16where said movement ruptures the flexible barrier.
 19. A packagedproduct according to claim 1 wherein said substance insert comprises aninterface for mechanical engagement with said container.
 20. A packagedproduct according to claim 19 wherein said interface is a deformableframe attached to said flexible barrier, such that deformation of saidframe translates into movement of said second compartment whichjeopardizes integrity of said flexible barrier. 21-155. (canceled)